Project Summary Osteoporosis is a major public health problem affecting 44 million Americans and costing an estimated $17 billion in 2001. Bone fractures in the elderly in particular can result in significant morbidity and mortality. Understanding the renal mechanisms that underlie bone loss in aging is the focus of this application. The kidney is responsible for Vitamin D synthesis and contributes to the control of calcium and phosphate levels. Bone-produced FGF23 and its co-receptor, ?Klotho help to regulate these processes, and dysregulation in these factors or any of their downstream signals can lead to bone loss. Aging also impairs kidney function which may also contribute to aging-related bone loss. However, whether the bone can affect kidney function is not known. Tryptophan, one of nine essential amino acids, is a potent anti-oxidant but its levels decrease with aging; however, its stable oxidized metabolite, kynurenine increases with age and inhibits bone marrow stem cell proliferation. Work from our laboratory has shown that kynurenine feeding in mice results in bone loss. Our central hypothesis is that augmented kynurenine levels induce an aged phenotype resulting in both bone loss and kidney dysfunction through the FGF23/?Klotho pathway. Dr. Irsik will conduct these experiments under the mentorship of Dr. Wendy Bollag, who has expertise in signal transduction and has been continuously VA Merit-funded for a dozen years. In order to gain knowledge in aging research, she will work towards a certificate in gerontology and collaborate with the members of her career advisory committee to gain expertise in experimental design in aging studies. Dr. Isales will provide expertise in aging and bone research while Dr. Carbone is an expert in bone issues in veterans and Dr. Dong is recognized for his research in acute kidney injury. Dr. Irsik will expand her current research skills by learning to perform DXA, ?CT and bone histology through the collaborative efforts of Drs, Bollag and Isales. Dr. Dong will provide assistance in her renal studies, and Dr. Carbone will teach her how to work with large datasets available through the VA. She will interact weekly with all the members of the Bone Group, comprised of both clinicians and basic scientists from multiple departments and disciplines, presenting her own research twice a year. She will present her research at a minimum of two international meetings per year (ASBMR, ASN, GSA or Experimental Biology). Her transition to independence will be enhanced by the mentorship of Dr. Bollag, who has guided many trainees to successful careers in academic research. She provides the perspective of a successful woman PhD scientist while Dr. Isales is a clinician who has advocated for under-represented minority researchers for many years. Together these two investigators, who have a successful track record of collaborating for approximately 30 years, will help to ensure that Dr. Irsik receives the mentoring necessary to be well-prepared for an independent research career in aging. This CDA2 award will be leveraged to obtain the preliminary data necessary for her to apply for her own VA Merit Award, thereby allowing her to obtain her first tenure-track faculty position.